We found previously that two naturally occurring peptides, arginine-8-vasopressin (AVP) and neuropeptide tyrosine (NPY) both decreassed coronary blood flow (CBF) by 36-41% without changing aortic blood pressure (AoP) after infusion directly into the coronary arteries of chloralose-anesthetized, open-chest dogs. Most importantly, we found that the vasoconstriction due to both AVP and NPY was severe enough to produce myocardial ischemia, as shown by impaired left ventricular contraction and development of tissue acidosis. We hypothesized that these peptides caused ischemia by constricting large coronary arteries remote from the ischemic cells which produce vasodilator-metabolites. We tested this hypothesis in 12 dogs prepared like the groups which demonstrated ischemia due to peptides. Resistances of large (R-L) and small (R-S) coronary arteries were calculated by dividing the respective pressure drops by the CBF, after a small, distal coronary branch was cannulated to measure distal coronary pressure (DCP). Intracoronary administration of AVP and NPY decreasd CBF by 41-48% without changing AoP or DCP. These were the same peptide doses that had produced mycardial ischemia. R-L increased from 0.22 to 0.39 units and R-S from 2.70 to 5.29 units (p. Less than .05 for R-S but not for R-L). More importantly, the change in R-S accounted for 93-94% of the change in total resistance (R-L + R-S). Thus the peptide-induced vasconstriction was due primarily to the constriction of smal coronary arteries, not the large arteries. These findings indicate the strength of vasoconstriction due to AVP and NPY because both peptides compete directly with the vasocilator metabolites near the small arteries or arterioles involved in normal regulation of CBF. We conclude that constriction of small coronary arteries can overcome the powerful processes that normally regulate small coronary arteries to control blood flow. This small vessel vasocontriction can produce myocardial ischemia.